The present work provides an overview of the different methods used in molecular diversity analysis. Issues like identifying voids in proprietary databases, reducing the number of redundancies present in databases, or designing focused libraries by grouping compounds similar to a template with the aim to fine tune its properties, are potent diversity analysis tools that may be used to optimize molecules based on their properties and specifically, to speed up the process of lead discovery and optimization. The present work describes first methods that are used to describe molecular systems. This is followed by a section devoted to describe different measures of similarity between molecules, to finish with a description of different methods used to select subsets molecules according to the constraints imposed. The final section deals with the validation of these methods, based on different studies available in the literature.

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis.